Several intermediate biomarkers have been linked to specific steps of human carcinogenesis, and these biomarkers have been associated with risk for cancer. This proposed study will focus on intermediate biomarkers measuring drug and procarcinogen metabolism (cytochrome P450 and glutathione S-transferase), binding of agents to DNA and DNA repair (DNA Binding, UDS and ADPRT) and cell proliferation (ODC and [(3)H]thymidine incorporation). The primary aim of this study is to develop and to compare the experimental testing of these biomarkers of cancer susceptibility in human mononuclear leukocytes and in the epithelium giving rise to breast and colorectal cancer ("target tissue"). The working hypothesis is that the measurements of these biomarkers in human mononuclear leukocytes may partially reflect the biological responses in target tissues. The correlation between measurements in leukocytes and target tissues will be investigated. The secondary aim is to explore the possible application of these intermediate biomarkers in measuring the biological responses to chemopreventive agents. The correlation between changes in leukocytes and the target tissue will be analyzed as well as the beneficial effects of different agents. Furthermore, the correlation between changes in different markers will also be evaluated. This analysis will provide evidence demonstrating that certain markers are regulated similarly by the same agent. Two groups of potential chemopreventive agents that will be tested in exploratory human trials initially include antiestrogen (tamoxifen) and antioxidants (vitamin C and beta-carotene). The Institutional Plan: CPRI has ongoing funded case-control, cohort, and intervention research; the ultimate aim of all of CPRI's research is to lower risk for cancer in humans. This research leads directly into Dr. Hu's proposal. CPRI has had and will continue to have persons paid to advise and support Dr. Hu in laboratory and field disciplines. The proposed study meets the award's criteria of "...development and experimental testing of hypothesis about cancer prevention and control in people, through the stage of confirming results using defined populations, to the development and demonstration of cancer control technology". The outcome of the human studies will validate the potential usefulness of these biochemical measurements in human leukocytes as markers to predict the beneficial effect of a given agent in future cancer intervention trials developed by our Institute.